1. Field of the Invention:
This invention relates to bleomycinic acid and to a process for preparing same.
2. Description of the Prior Art:
Bleomycin, antitumor antibiotics are water-soluble basic glycopeptides which are chelated with divalent copper, and are produced from Streptomyces verticillus. They were first discovered by Hamao Umezawa, et al., in 1966, and reported in Journal Of Antibiotics 19A, Page 200 (1966).
Sixteen varieties of bleomycins, including 3-dimethylsulfopropylamino-bleomycin(bleomycin A.sub.2) and 4-guanidinobutylamino-bleomycin (bleomycin B.sub.2), have been produced and isolated by conventional cultivation methods including bleomycin A.sub.1, A.sub.2, A.sub.5 and B.sub.2. These latter varieties have been used in complex form for the treatment of cancroid, malignant lymphoma and cerebral tumors, and exhibit antitumor effects and broad cancer indications.
By hydrolysis techniques, the chemical analysis of the bleomycins have been noted as follows: ##STR1##
The various types of bleomycins differ by differing terminal amino group "R". In the present invention, R is an --OH group. Many of the bleomycins have the same basic nucleus but different side chain amines. The microbial activity, antitumor activity and other physiological activity of these closely related bleomycins, however, are quite different, depending upon the particular amine side chain R in the formula.
When the bleomycin-producing strain of actinomycetes is inoculated and cultivated in a nutritious medium, bleomycins can be produced as complexes of bleomycin A.sub.1, A.sub.2, A.sub.5, B.sub.2, etc. If an amine, which corresponds to the side chain amine of the intended bleomycin is added, as a precursor, a bleomycin having the corresponding amine can be produced. Of course, the particular type of amine used is limited by ordinary considerations of biosynthesis, so that the range of possible amine derivatives attainable has been particularly limited. The type of biological activity will substantially vary, depending upon the particular variety of bleomycin and hence methods of developing different varieties are continually being sought.
To attain a wider latitude in the preparation of new amine derivatives, it was first contemplated to sever the side chain of the bleomycin without altering the basic nucleus structure, by enzyme reaction. It was found, however, that bleomycin cannot be used as a substrate for commercial or available hydrolysis enzymes such as peptidase, protease, pepsin, .alpha.-chymotrypsin, pronase, phytin, and amino acid acylase, and no severing of the side chain occurred.
Other microorganisms were studied as a means for producing an enzyme which would sever the side chain of bleomycin, and a wide variety of bacteria, actinomycetes and molds were considered.
It has now been discovered that specific mycelium molds having high decomposition activites can be used to provide an enzyme reaction which will provide novel bleomycinic acid compounds.